JPS61243068A - Fluorinated 1-(alpha-phenylalkyl)-1h-1,2,3-triazole compound and manufacture - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The invention relates to formula (I): in which ph represents a phenyl residue fluorinated in the 0-position and optionally further substituted with at least one further halogen atom, and alk is represents a lower alkylidene,
Novel fluorination 1 of: R1 represents hydrogen, lower alkyl, or a carbamyl group unsubstituted or substituted with lower alkanoyl or lower alkyl, and R2 represents a carbamyl group unsubstituted or substituted with lower alkanoyl or lower alkyl. -(α-7enylalkyl)-1H
The present invention relates to -1,2,3-) lyazole compounds, methods for producing the novel compounds, pharmaceutical preparations containing them, and uses thereof.

Further halogen substituents of ph include, for example, halogen atoms with atomic number up to 35, such as fluorine, chlorine or secondarily bromine. A total of up to five halogen substituents may be present, but in addition to the 〇-fluorine substituents,
For example, 1 or 2 chlorine atoms, 1 chlorine atom and 1
fluorine atoms, optionally from 1 to 3 or less, for example 1 or 2 fluorine atoms, may be present. Each further halogen atom is thus bonded, for example, in the 4-15- or especially in the 6-position.

Lower alkylidenes include, for example, C1-04-alkylidenes, especially methylene, but also ethylidene, 1,1-propylidene, 2,2-propylidene (impropylidene) or 1,1-butylidene.

Lower alkyl is, for example, C,-C4-alkyl, such as methyl or secondarily ethyl, propyl, isopropyl, butyl, isobutyl, 5eC-butyl or tert-butyl, and also C3-C,-alkyl, For example, pentyl.

It has a hexyl or heptyl group.

Lower alkanoyl or carbamyl substituted with lower alkyl is especially monosubstituted with lower alkanoyl or disubstituted with lower alkyl, for example N-C,
-C,-alkanoylcarbamyl, primarily N-C2-C
,-alkanoylcarbamyl, such as acetylcarbamyl or pivaloylcarbamyl, or especially N,
N-diC,-C4-alkylcarbamyl, e.g.

It means N,N-dimethylcarbamyl or N,N-diethylcarbamyl.

This new compound has valuable pharmacological 7M properties, in particular pronounced antispasmodic semi-active activity, which, for example, is based on the pronounced metrazole antagonism in mice, about 30 to 30
00 mg/kg p,o, and based on the pronounced protective effect against electric shock-induced spasticity in mice and rats as well, approximately 1
to 50 mg/kgp, 0. A dose range of 1 to 25 mg/kg p,a is often demonstrated. In this test, for example, mg/
The following values were obtained for the effective dose EDso expressed in kg orally (administered 1 hour before the test).

1-(2,6-difluorobenzyl)-1H-1,2,
3-triazole-4-carboxamide: 17 (mouse) or 8 (rat); 1-(o-fluorobenzyl)-1H-1,2.

3-triazole-4-carboxamide: 17 (mouse, rat); 1-(2,6-difluorobenzyl)-1H-1,2,
3-triazole-4,5-dicarpoxamide = 4 (mouse, rat); 1- (6-rioa-2-fluorobenzyl)-1H-
1,2,3-triazole-4,5-dicarboxamide: 7 (mouse) or 10 (rat).

1-(o-fluorobenzyl)-1H-1,2.

3-triazole-4,5-dicarpoxamide: 6 (mouse) or 10 (rat): 1- (6-]｝o-2-fluorobenzyl)-1H
-1,2,3-triazole-4-carboxamide: 1
1 (mouse): 1-(2,5-difluorobenzyl)-1H-1,2,
3-triazole-4,5-dicarboxamide: 6 (mouse) Fluorinated 1-(α-
The phenylalkyl)-1H-1,2,3-triazole compounds have the advantage of improved activity compared to known chlorinated analogues having antispasmodic activity. That is, in the above test, for example, the following ED
SO-values were obtained.

1-(o-chlorobenzyl)-1H-1,2,3-triazole-4-carboxamide: 26 (mouse) or 2
5 (rat) and 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide: 40 (mouse)
or 43 (rat).

The compounds prepared according to the invention are therefore highly suitable for the treatment of spasticity of various causes, for example for the treatment of epilepsy, and are used as antispasmodic, for example antipruritic, isotropic pharmacological agents.

The present invention firstly relates to phenyl of the formula (I), in which pH represents a phenyl fluorinated in the 0-position and optionally further substituted with up to 3 halogen atoms with an atomic number up to 35;
alk represents C1-C4-alkylidene, R, is hydrogen, C,-C4-alkyl, carbamyl, N C1-C
7-alkanoylcarbamyl or N,N-diC1Ca
- represents alkylcarbamyl, R2 is carbamyl, N-
C1-C,-alkanoylcarbamyl or N,N-di-C1-c4-alkylcarbamyl).

The present invention preferably comprises formula (I) (wherein the pH is fluorinated at the Phenyl substituted with fluorine atoms, such as o-fluorophenyl, 2,3-12.4-12,5- or 2,6
-difluorophenyl, 2-chloro-6-fluorophenyl, and further represents 2,4.6-)lifluorophenyl,
alk represents c, -Ca-alkylidene, for example methylene, furthermore ethylidene or 2,2-propylidene, R
, is hydrogen; C, -C4-alkyl, such as methyl; carbamyl, N-C2-c, -alkanoylcarbamyl,
for example acetyl- or pivaloylcarbamyl; or N,N-diC,-C4-alkylcarbamyl, for example dimethylcarbamyl, and R2 is carbamyl; N
-C2-C,-alkanoylcarbamyl, e.g.

Acetyl- or pivaloylcarbamyl; or N, N
-diC□-C4-alkylcarbamyl, for example dimethylcarbamyl).

The invention particularly relates to compounds of formula (I) in which pH is fluorinated in the 0-position and optionally further contains one chlorine atom, one fluorine atom and one chlorine atom, or up to two fluorine atoms. Substituted phenyl, such as o-fluorophenyl, 2.3-.2.4-.2.5- or 2.6-difluorophenyl, 2-chloro-6-fluorophenyl, and also 2.4 .represents rottrifluorophenyl, a
lk is C,-C4-alkylidene, especially 1, t-c
l-C4-alkylidene, for example methylene; R
1 represents hydrogen, C□-04-alkyl, e.g. methyl, or a residue R2, R2 is carbamyl or secondly N-C
2-c,-alkanoylcarbamyl, e.g. acetylcarbamyl: or N,N-dic,-c4-alkylcarbamyl, e.g. , pH is o-fluorophenyl, 2.3-.2.4-.2.5- or 2.6-
difluorophenyl or 6-chloro-2-fluorophenyl, alk represents methylene, R1 represents hydrogen or unsubstituted carbamyl, and R2 represents unsubstituted carbamyl.

The invention particularly relates to compounds of the formula (I) in which ph represents o-fluorophenyl or 2,6-difluorophenyl; al
k represents methylene, R□ represents hydrogen or unsubstituted carbamyl, and R2 represents unsubstituted carbamyl.

The present invention preferably uses the formula (■) (wherein the pH is 2.6-
represents difluorophenyl, alk represents methylene, R1 represents hydrogen, c, -Ca-alkyl, such as methyl, or a residue R2, R2 is carbamyl; mil, e.g. acetylcarbamyl; or N,N-diC,-C,-alkylcarbamyl, e.g. dimethylcarbamyl)
Concerning the compound.

The present invention first relates to formula (I) (wherein pH is 〇-fluorophenyl, 2,5-difluorophenyl, 2.6-
represents difluorophenyl or 2-chloro-6-fluorophenyl, alk represents methylene, R1 and R2
both represent carbamyl), furthermore a compound of formula (I) (wherein pH represents 2,6-difluorophenyl, al
k represents methylene, R1 represents hydrogen or carbamyl, and R2 represents carbamyl).

The compound of formula (I) can be prepared by a method known per se, for example, a) Ph-alk-N3(II) is converted to formula (■): Y, Y2, where Yl represents hydroxy and Y2 represents hydrogen. , or Yl and Y2 together represent a further bond.

or a salt thereof and/or a tautomer thereof, or b) formula (■): Ph -alk -Z (IT) in which:
Z represents a reactive esterified hydroxy compound, is reacted with a 1H-1,2,3-) lyazole derivative of formula (V) or a salt thereof, or C) formula (■): where, Y4 is a residue YA that can be converted to unsubstituted or lower alkyl-substituted carbamyl.

Y5 is the group R1 or a residue YB which can be converted into carbamyl unsubstituted or substituted with lower alkyl, or Y4 is the group R2 and Y5 is a residue YB which can be converted into carbamyl which is unsubstituted or substituted with lower alkyl. In the compound represented by, Y and/or YB are converted to unsubstituted or lower alkyl-substituted carbamyl, and if necessary, the resulting isomer mixture is separated into each component to obtain the isomer of formula (I). If desired, the compounds obtained by each method are converted into other compounds of formula (I) and/or the enantiomeric or diastereomeric mixtures obtained by each method are converted to each component. It can be manufactured by dividing it into two parts.

Examples of starting materials of formula (m) and tautomers thereof for the compound "L3-" include the formula: R□-C-aC-R2 (
Ha) Formula: RI C(=O) CH2-R2(m
Examples include compounds b). These salts are, for example, alkali metal salts, such as sodium salts, of compounds of formula (ma), obtained from compounds of formula (Ha) and alkali metal alkanolades, such as sodium methanolade.

Compound (II) and compound (II[) are reacted in a conventional manner.

It is preferably carried out in a fluorine-active solvent, if necessary in the presence of a condensing agent and/or under heating. Inert solvents are, for example, aromatic or araliphatic hydrocarbons, such as penzole or doluol, or ethers, such as tert-
Butoxymethane, tetrahydrofuran or dioxane.

In a preferred embodiment of this method, for example, the formula (
The azide of II) is reacted with a compound of formula (ma) in penzole or dioxane at about 60 DEG to 120 DEG C., preferably at the boiling point.

The starting materials of formula (m) and some of formula (II) are known. The new starting materials of formula (II) can be prepared by methods analogous to those for the preparation of known substances, for example, formula Ph-alk-Z (IV
) (wherein Z is a reactive esterified hydroxy, e.g.
Halogens, such as chlorine, bromine or iodine, or sulfonyloxy, such as lower alkanesulfonyloxy, optionally substituted benzenesulfonyloxy, such as methane-, ethane-, benzene-1p-toluene- or p-bromobenzene. sulfonyloxy or fluorosulfonyloxy) with an alkali metal azide, such as sodium azide,
For example, by reacting in dimethyl sulfoxide or dimethyl formamide, or by reacting alcohols (2=hydroxy) with hydrazoic acid in the presence of triphenylphosphine and azodicarboxylic acid esters, e.g. For example, it can be obtained by a method of reacting in doluol.

In the starting material for the modified L, the reactive esterified hydroxy can be, for example, a halogen, such as chlorine, bromine or iodine, or a sulfonyloxy, such as lower alkanesulfonyloxy, an optionally substituted benzene. Sulfonyloxy, e.g. methane, ethane, bene, P-)luene or P-/'
It means lomobenzenesulfonyloxy or fluorosulfonyloxy.

Salts of compounds (V) are, for example, their alkali- or alkaline-earth metal salts, such as sodium, potassium or calcium salts.

This reaction is carried out in a customary manner, for example in the presence of a basic condensing agent, advantageously with the component of formula (V) as a salt, if necessary with heating, preferably in a solvent or diluent. The basic condensing agent is, for example, a basic condensing agent that forms a salt with the component of formula (V), for example, an alkali metal alcoholade, for example,
Sodium methanolade or sodium ethanolade; alkali metal or alkaline earth metal amides, such as sodium amide or lithium diisopropylamide. As mentioned above, it is advantageous to carry out the conversion beforehand into the components of formula (V) and their salts, for example by reaction with one of the bases mentioned above. The solvent is preferably a corresponding alcohol when the reaction is carried out in the presence of alcoholades, and an aprotic organic solvent such as a lower phosphoric acid when carrying out the reaction in the presence of amides. Alkylamides, e.g.
Hexamethylphosphoric acid triamide; Alkanoic acid amides 1
For example, dimethylformamide; or di-lower alkyl sulfoxides, such as dimethyl sulfoxide.

With each method, isomers formed as by-products are separated, if necessary, from the desired compound of formula (I).

If the starting materials (rV) and (V) are not already known, they can be produced by conventional methods. That is, the compound of formula (IV) can be prepared by, for example, converting the corresponding alcohol (■; Z=hydroxy) into, for example, thionyl chloride,
It is obtained by converting it into a reactive ester using phosphorus tribromide or sulfonyl chloride. Compound (V) is obtained by reacting trimethylsilyl azide or hydrazoic acid with a compound of the formula: % formula %) in which R represents carbamyl, particularly unsubstituted or substituted with lower alkyl, and then optionally If desired, the silyl group of the 1-trimethylsilyltriazole derivative, as is the case with the compound of formula (II) described below, is removed by mild hydrolysis after lower alkylation (lower alkanoylation) of carbamyl R2 and/or R1. It can be manufactured by removing. trimethylsilyl azide with the formula: %formula%) in which Y4 represents a residue YA which can be converted into unsubstituted or lower alkyl-substituted carbamyl, e.g. esterified carboxy, e.g. lower alkoxycarbonyl, or cyano; Y5 is hydrogen or a residue Y convertible into carbamyl, preferably unsubstituted or substituted with lower alkyl, preferably identical to YA, and then in the case of esterified carboxy, For example, by ammolysis (reaction with ammonia) or, in the case of cyanide, by hydrolysis, e.g.
It is also possible to convert Y and/or YB to unsubstituted or lower alkyl-substituted carbamyl, in which case the trimethylsilyl group is also removed.

Residues YA and/or YB which can be converted into carbamyl, unsubstituted or substituted with lower alkyl, for example "carboxyl radicals present in free or salt or anhydride form" group, an unsubstituted or lower alkyl-substituted amidino group or an esterified carboxy group,
Furthermore, it is a cyano group.

An esterified carboxy group is a carboxy group esterified with, for example, lower alkanols or lower alkyl mercaptans, i.e. a lower alkoxy- or lower alkylthiocarbonyl group, but also optionally with any other alcohol or mercaptan, e.g. It may be esterified with substituted phenols or thiophenols.

Carboxy groups present in the form of salts include, for example, carboxy groups present in the form of ammonium salts derived from ammonia or di-lower alkylamines, and also in the form of metal-1, e.g. alkali- or alkaline earth metal salts. Carboxy group present.

Carboxy groups present in anhydride form are, for example, carboxy groups present in halide form, such as chlorocarbonyl, but may also be anhydrified with reactive carboxylic acids, for example alkoxycarbonyloxy. Means carbonyl or trifluoroacetoxycarbonyl.

The conversion of the aforementioned radicals Y and/or YB into optionally lower alkylated carbamyl can be carried out in a customary manner by converting carboxy groups present in free, esterified or anhydrous form and unsubstituted or substituted with lower alkyl. Starting from the converted amidino group, it is carried out by solvolysis, ie hydrolysis, or by ammonolysis or amitolysis (reaction with ammonia or di-lower alkyl amines).

By hydrolysis, for example, a cyano group in carbamyl or an unsubstituted or lower alkyl-substituted amidino group YA and/or YB can be converted into an unsubstituted or lower alkyl-substituted carbamyl group. Hydrolysis of the cyano group can be carried out, for example, in the presence of basic hydrolyzing agents, such as alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, and if necessary with peroxide compounds, such as peroxide. Hydrolysis of the amidino group, carried out in the presence of hydrogen, can be carried out, for example, using acidic hydrolyzing agents, such as mineral acids,
Preferably in the presence of a sulfonic or carboxylic acid, such as sulfuric acid, phosphoric acid, hydrochloric acid or other hydrohalic acids, p-)cyansulfonic acid or other organic sulfonic acids, or lower alkanoic acids, such as acetic acid, preferably as a catalyst. carried out in the presence of a quantity.

By ammolysis or amitrilysis, for example, a free or esterified carboxy group present in salt or anhydride form can be converted into unsubstituted or lower alkyl-substituted carbamyl. that time,
The condensing agent is preferably carried out in an inert solvent, if necessary in the presence of a condensing agent, which is a basic condensing agent, in particular ammonia, or an excess of the amine used in the amitrilysis, present in anhydrous form. Starting from the carboxylic acid, further with alkali metal hydroxides or alkali metal carbonates or tert-organic nitrogen bases, such as tri-lower alkylamines or tert-heteroaromatic nitrogen bases, such as triethylamine or pyridine. be. The free carboxy group is removed by dehydration of the intermediately generated ammonium salt,
For example, heating or dehydrating agents such as acid anhydrides, e.g.
Phosphorous pentoxide, etc., or carbodiimides, such as N
.

Due to the action of N'-dicyclohexylcarbodiimide,
Can be converted to carbamyl. A particularly preferred embodiment of each variant is to add an excess of ammonia or a di-lower alkyl R
2 and optionally R1 is lower alkanoylated.

The starting material of formula (VI), if not known, can be prepared in the usual way, for example by formula (II): Ph-alk-N
s (II) azide of formula (■a) or (
■b): y5-c=c-y4 (■a) or R, -C (=0)
It can be produced by reacting with a compound of CH2-Ya (■b), for example, in the same manner as described in variant a). If necessary, from the beginning, the obtained esters or nitriles of formula (■) (wherein YA and optionally Yn are esterified carboxy or cyanide) are added under basic conditions, for example, using an alcoholic caustic soda aqueous solution. formula (■) obtained from scratch after hydrolysis to the corresponding acid or by hydrolysis of the corresponding esters or nitriles (in which YA and optionally Y
B is carboxy) can be converted to its acid chloride, for example with thionyl chloride.

・The next door to the next door
In particular, substitution with N-unsubstituted or N-mono-lower alkylated carbamyl groups R2 and/or R1 and separation of the isomer mixtures obtained by the respective methods are mentioned.

That is, in the compound of formula (I), N-unsubstituted rubamyl is converted to N by treatment with a lower alkanoylating agent.
- lower alkanoylcarbamyl, or unsubstituted carbamyl to N,N-di-lower alkylcarbamyl by treatment with a lower alkylating agent and/or N-mono-lower alkylcarbamyl to N,N-di-lower alkylcarbamyl; N-mono-lower alkyl derivatives of compounds of formula (I) that can be converted into mils are, for example, the corresponding formulas (m), (V
) or (■), especially starting from the starting material (VI).

Lower alkanoylating agents are, for example, lower alkane carboxylic acid anhydrides, such as acetic anhydride or mixed anhydrides of formic acid and acetic acid, or lower alkane carboxylic acid chlorides, such as acetyl chloride. The process is carried out, if desired, in the presence of a base, such as triethylamine or pyridine, and, in the case of reactions with acid anhydrides, in the presence of mineral acids, such as sulfuric acid.

Lower alkylating agents are, for example, reactive esters, such as hydrohalic acid monosulfuric acid or sulfonic acid esters of lower alkanols, such as lower alkyl halides, such as methyl iodide, di-lower alkyl sulfates. , for example dimethyl sulfate, or lower alkyl esters of aliphatic or aromatic sulfonic acids, especially lower alkanesulfonic acids or optionally substituted benzenesulfonic acids, for example,
They are lower alkyl methanesulfonate esters, lower alkyl ethanesulfonate esters, lower alkylbenzenesulfonate esters, or lower alkyl-P-toluenesulfonate esters. This lower alkylation is carried out in a conventional manner, for example under basic conditions, for example in the presence of alkali metal hydroxides, for example potassium hydroxide.
and, if desired, in the presence of a phase transfer catalyst, such as tetrabutylammonium bromide or benzyltrimethylammonium chloride.

As isomer mixtures, for example, enantiomeric or diastereomeric mixtures of compounds of formula (I) with at least one asymmetric carbon, as well as isomers thereof formed with compounds of formula (I) by the respective methods; The isomer mixtures can be separated by conventional methods. Diastereoisomers as well as mixtures of the compounds of formula (I) and their isomers formed by each method can be separated by conventional physical separation methods, e.g. fractional crystallization, e.g. on the basis of the different physical properties of the components. It can be separated by chromatography or the like. For the separation of normal body mixtures, e.g.
Fractionation from optically active solvents 11
P/T71↓'-phase 4 fR1,- chromatography is suitable. Alternatively, the enantiomer mixture can be converted into the corresponding diastereomeric acyl derivative, for example by reaction with optically active acid chlorides, and each component from which they can be isolated, for example, by mild acid treatment to give the pure substance.

For example, new starting materials of formula (V) and (VT) which have been specifically developed for the preparation of uninvented compounds, in particular starting materials for the preparation of compounds of formula (I) as preferred , their production process and their use as intermediate products are likewise an object of the invention.

The novel compounds of formula (I) can be administered, for example, by administering a therapeutically effective amount of the active ingredient, optionally by enteral administration, e.g. by oral administration,
Alternatively, it can be used in the form of a pharmaceutical composition containing an inorganic or organic, solid or liquid pharmaceutically acceptable carrier suitable for parenteral administration. The compositions used may therefore contain the active ingredients as diluents such as lactose, dextrin, sucrose, mannitol, sorbitan, cellulose and/or glycine; and/or lubricants such as silica, talc, stearic acid or its salts, e.g. , magnesium stearate or calcium stearate; and/or polyethylene glycol. The tablets may also contain binders such as aluminum aluminum silicate, starches such as corn, wheat, rice or arrowroot starch; gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose;
and/or polyvinylpyrrolidone and, if desired, disintegrants, such as starches, agar, alginic acid or its salts, such as sodium alginate; and/or effervescent mixtures; or adsorbents; colorants; flavorings and sweeteners. It also contains ingredients. The novel compounds of formula (I) can also be used in the form of compositions for parenteral administration or injectable compositions. The solutions are preferably isotonic aqueous solutions or suspensions, which may be prepared before use, for example in the case of lyophilized preparations containing the active ingredient alone or together with a carrier such as mannia). I can do it. The pharmaceutical composition can be sterilized and/or contain adjuvants, such as preservatives, stabilizers, lubricants and/or emulsifiers, solubilizers, salts for adjusting the osmotic pressure and/or buffers. May be contained. The pharmaceutical compositions according to the invention can, if desired, further contain pharmacologically active substances and can be prepared by methods known per se, such as conventional mixing, granulating, confectionery, dissolution or freeze-drying methods. and contains about 0.1 to 100%, preferably about 1 to 50% (lyophilized to I00%) of active ingredient.

The present invention also provides compounds of formula (I), preferably in the form of a pharmaceutical composition.
Concerning the use of the compound. The dosage depends on various factors, such as the method of administration, the species, the age of the patient and/or the individual condition. The daily dose for oral administration is approximately 1-50 mg
/ kg, with a single dose of approximately 1-25 mg/kg.
kg, and for a warm-blooded animal weighing approximately 70 kg,
Preferably the daily dose is about 0.070-3.5g.

The following examples are intended to illustrate the invention. Temperatures are shown in degrees Celsius.

Real m1- (o-fluorobenzyl)-1H-1,2,
Dimethyl 3-triazole-4,5-dicarboxylate '7
3.5g (o, 25mol) of methanol 1000+rJ
dissolved in. 250 g of ammonia were then introduced under pressure into the autoclave and the reaction mixture was heated to 100 g for 24 hours.
It was kept at ℃.

The patch is then cooled and the crystallized product is suction filtered.
Washing with methanol and recrystallization from dioxane/toluene yielded 1-(o-fluorobenzyl)-1H-1,2,3-triazole- with a melting point of 197-199°C.
4,5-dicarboxamide was obtained.

The starting material can be prepared as follows: A solution of 40 g (o, 282 mol) of dimethyl acetylenedicarponate in toluene (500 mJ) is added to 0-fluorobendi, 1-fluorobendi, which has been heated to 90°C.・,1-,L'A
lC-#/l'1QC-C-1-1-)/F%L+1,
It was added dropwise to the solution. After a further 5 hours at 90° C., the toluene was removed, the reaction mixture was cooled and the crystalline product was filtered off with suction. Recrystallization from a 1:1 mixture of diethyl ether/petroleum ether gives a melting point of 49~
1-(o-fluorobenzyl)-1H-1,2 at 51°C
, 3-triazole-4,5-dicarboxylic acid dimethyl was obtained.

1-1-1-(o-fluorobenzyl)-1H
-1,2,3-triazole-4,5-carboxylic acid 59
g (o, 26 g) and thionyl chloride 300- were heated to reflux for 1 hour. Excess thionyl chloride was distilled off in vacuo, leaving a residue 1-(o-fluorobenzyl)-1H-1,2
, 3-triazole-4-carboxylic acid chloride was dissolved in 500% of toluene. This solution was added dropwise to 500 ml of concentrated aqueous ammonia solution at 5-10°C. The precipitated product was filtered with suction, washed with water, and recrystallized from ethanol to give 1-(o-fluorobenzyl-1H-1,2,3-triazole-4-carboxamide) with a melting point of 220-222°C. - The starting material can be prepared as follows: 50 g (o, 33 mol) of 0-fluorobenzyl azide,
23.1 g (o, 33 mol) of propynecarboxylic acid and 400 g of toluene were stirred for 24 hours at 70°C. After cooling the reaction mixture to room temperature, the precipitated product was filtered with suction and washed first with toluene and then with diethyl ether. 3-triazole-4-carboxylic acid was obtained.

Example 1 - 1 - By the procedure described in Example 1, 1-(2,6-difluorobenzyl)-1H-1,2, 3-triazole-4,5
-via dimethyl dicarboxylate, melting point 203-205℃
1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4,5 (recrystallized from methanol)
-Dicarboxamide was obtained.

Example 1 - Lifetime 2 - By the procedure described in Example 2, 2,6-cyfluorobenzyl azide with a melting point of 160
1- at ~162°C (recrystallization from acetonitrile; decomposition)
(2,6-difluorobenzyl)1H-1,2,3-triazole-4-carboxylic acid, melting point 237-24
1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4 at 0°C (recrystallized from ethanol)
- A carboxamide was obtained.

Examples 1-5 - The following compounds can also be prepared according to the procedures described in Examples 1-4: 1-(2
, 3-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide.

1-(2,4-difluorobenzyl)-1H-1,2,
3-triazole-4-carboxamide and 1-(2,5-difluorobenzyl)-1H-1,2,
3-triazole-4-carboxamide.

I by the operation described in Example 1 - Moxibustion Example 2
J, 1-(6-chloro-2-fluorobenzyl)-1H
-1,2,3-triazole-4-carboxylic acid with mp 274-276°C (recrystallized from glacial acetic acid)
-chloro-2-fluorobenzyl)-1H-1,2,3
-triazole-4-carboxamide was obtained.

The starting material can be prepared as follows: 98 g of 6-chloro-2-fluorotoluene (o,678
mol), sulfuryl chloride 91, 5 g (o, 678 mol) and dibenzoyl peroxide 0.2 g for 3 hours i.
When stirred at oo~110°C and then distilled, Sdp,
6-chloro-2-fluorobenzyl chloride having a boiling point of 15 = 78-82°C was obtained.

123 g of 6-chloro-2-fluorobenzyl chloride (
o, 687 mol) and 47 g of sodium azide (o, 7 mol)
22 mol) in dimethyl sulfoxide (400d) at 20-40°C. The mixture was stirred for 4 hours at room temperature, then diluted with ice water and extracted with cyclohexane. When the solvent was distilled off and the residue was distilled, 6-chloro-2-fluorobenzyl azide (bP1s=99~
100''C) was obtained.

27.5 g of 6-chloro-2-fluorobenzyl azide (
o, 15 mol) and 10-5 g of propynecarboxylic acid (
o, 15 mol) in toluene (300+J) was heated at 90"C for 3 hours. After cooling, the crystals were filtered with suction and recrystallized from acetonitrile, giving a melting point of 182 °C.
(Decomposition) of 1-(6-chloro-2-fluorobenzyl)
-1H-1,2,3-triazole-4-carboxylic acid was obtained.

Practical Example--1 By the procedure described in Example 1, 1-(6-chloro-2
-fluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl, melting point 214
1-(6-chloro-
2-fluorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxamide was obtained.

11JL Once two-by the operations described in Example 1,
2,5-difluorobenzyl azide (b,p 5=82
~84°C) to 1-(2,5-difluorobenzyl)
-1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl, 1-(2,5-difluorobenzyl)-1H-1, melting point 191-192°C (recrystallized from dioxane/toluene), 2,3-triazole-4,5
-Dicarboxamide was obtained.

Example 1 - By the procedure described in Example 1, 2,4-difluorobenzyl azide (bPts = 80
~83°C) to 1-(2,4-difluorobenzyl)- with a melting point of 75-76°C (recrystallized from cyclohexane).
1-(2,4-difluorobenzyl)-1H-1,2 with a melting point of 183-185°C (recrystallized from dioxane/toluene) via dimethyl 1H-1,2,3-triazole-4,5-dicarboxylate ,3-triazole-4,5-
Dicarboxamide was obtained.

By the operation described in Example 1, the melting point was 130-133°0 by reaction with dimethylamine.
N,N-dimethyl 1-(2,6-difluorobenzyl)-1H-1 (recrystallized from tert-butoxymethane)
, 2,3-triazole-4,5-dicarboxamide was obtained.

Actual Example 1 - 1 By the operation described in Example 1,
From 2.3-difluorobenzyl azide and dimethyl acetylene dicarboxylate, 1-(2,3-difluorobenzyl)-1H-1,2,3-triazole-4,5-
Via dimethyl dicarboxylate, melting point 183-185°C
(recrystallized from ethyl acetate/benzene) of 1-(2,3-
Difluorobenzyl)-1H-1,2,3-triazole-4°5-dicarboxamide was obtained.

LL Example 123 - By the procedure described in Example 2, 1
-(2,6-difluorobenzyl)-1H-1,2,3
- from triazole-4-carboxylic acid, melting point 208-2
1-(2,6-difluorobenzyl)-5-methyl-1H-1,2°3-triazole-4-carboxamide at 10°C was obtained.

The starting material is prepared as follows: Sodium2.
53 g (o, 11 mol) are dissolved in 60+ nl of alcohol, then 16.9 g of 2,6-cyfluorobenzyl azide
(o, 1 mol) and 14.3 g (o, 11 mol) of ethyl acetate in alcohol (60d) were added and the batch was heated to reflux for 16 hours. After addition of 120° of normal sodium hydroxide solution, the reaction mixture was refluxed for a further 2 hours, then diluted with 200° of water and acidified to pH 1 with hydrochloric acid while cooling. The precipitated product was filtered with suction, washed first with water and then with ether and dried to give 1-(2,6-difluorobenzyl)-5-methyl-1H-1,2,3 with a melting point of 166-167°C. -triazole-
4-carboxylic acid was obtained.

By the procedure described in Example 1, 1-(I-(2,6-difluorobenzyl)ethyl)
-1H-1,2,3-triazole-4-carboxylic acid ethyl 1-(I-(2,6=difluorobenzyl)ethyl)-1H-1° with a melting point of 205-207°C (recrystallized from methanol) 2.3-triazole-4-carboxamide was obtained.

The starting material is prepared as follows: 10.2 g (66 mmol) of 2.6-cyfluoroacetophenone are reduced with 2.5 g (65 mmol) of lithium aluminum hydride in ether to give 1- (2,6-difluorophenyl)ethanol is obtained as a colorless oil.

1-(2,6-difluorophenyl)ethanol 10g
(63 mmol) was dissolved in hydrogen azoic acid 150-(1.2N in toluene). Add 2 ml of trifluoroacetic acid to this solution.
2.8 g (200 mmol) were added and the reaction mixture was stirred to room temperature for 24 hours. After dilution with 300 WJ of hexane, the reaction solution was washed first with water and then with sodium bicarbonate solution until free of acid and dried over sodium sulfate. The solvent was subsequently removed under reduced pressure at 40-50°C. The residue was dissolved in 100-hexane and the solution was filtered through 50 g of silica gel and evaporated once more to give 1-(2,6-difluorophenyl)ethyl azide as a colorless oil.

1(2,6-difluorophenyl)ethyl azide 6.5
g (35 mmol) and 2.45 g of propynecarboxylic acid
A solution of (35 mmol) in toluene (50 rn) was heated at 60-70 °C for 24 h. The cooled reaction mixture was
Sodium hydroxide 100m! After extraction with
1-(I-(2,6-difluorophenyl)ethyl)
-1H-1,2,3-triazole-4-carboxylic acid was obtained.

1-(I-(2,6-difluorophenyl)ethyl)-
1H-1,2,3-triazole-4-carboxylic acid7.
1 g (26.6 mmol), 150+ J of ethanol and 1- sulfuric acid were heated to reflux for 10 hours. After post-treatment, 1-(I-(2
,6-difluorophenyl)ethyl)-1H-1,2,
Ethyl 3-triazole-4-carboxylate was obtained.

l-(2-(2-(2,
6-difluorophenyl)propyl]} -1H-1,
From ethyl 2,3-triazole-4-carboxylate, 1-
2-(2-(2.

6-difluorophenyl)furovir]}-1H-1,2
, 3-triazole-4-carboxamide was obtained.

The starting material is prepared as follows: 120 - 3 molar solution of methylmagnesium chloride in tetrahydrofuran is mixed with 2
．． It was slowly added dropwise to a solution of 28 g (I50 mmol) of ethyl 6-difluorobenzoate in ether (200 a/ml). 1 hour under reflux and then 1 hour with 10% ammonium chloride solution! Upon treatment, 2-(2,6-difluorophenyl)propane-2 with a boiling point of bp12 = 74-76°C
-Oar was obtained.

20.6 g (20 mmol of I) of 2-(2,6-difluorophenyl)propan-2-ol was added to an azohydrogen acid solution (
IN, in benzene) and 22.8 g (200 mmol) of trifluoroacetic acid were added to this solution. After standing at room temperature for 24 hours, the reaction solution was diluted with hexane 50
It was diluted with 0- and washed with water, then with sodium bicarbonate until free of acid, and dried over sodium sulfate.

When the solvent was removed by evaporation and the residue was distilled, 1) Pt
2-(2,6-difluorophenyl)-2-azidopropane with s = 85-87°C was obtained.

2-(2,6-difluorophenyl)-2-azidopropane Log (51 mmol) was converted to propynecarboxylic acid 3.
Reaction with 6 g (51 mmol) of toluene (I00a/) and work-up carried out as described in Example 12 yielded 1-(2
-(2-(2,6-difluorophenyl)propyl)}
-1H-1,2,3-triazole-4-carboxylic acid was obtained.

When the above acid is esterified using 50% of ethanol and 0.5% of concentrated sulfuric acid, 1-(2-(2-(2,6-difluorophenyl)propyl))-1H-1,2,3-triazole- Ethyl 4-carboxylate was obtained as a pale yellow viscous oil that could be used for reaction with ammonia without further purification.

Practical JL Example 1 By the procedure described in Example 1, 1-
(2-(2-(2,6-difluorophenyl)propyl)} -1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl (m, p, = 100-102°C
) to give 1-(2-(2-(2,6-difluorophenyl)propyl)}-1H-1,2,3-triazole with a melting point of 177-178°C (recrystallized from ethyl acetate/hexane) -4,5-dicarboxamide was obtained.

722,6-difluorobenzyl azide 16.9 g (o
, 1 mol) and but-2-ynecarboxamide 8.3 g
(o, 1 mol) in dioxane 20-100 for 16 hours
Heated at ℃. After removing dioxane by evaporation, the desired isomer was separated by column chromatography.
1- with a melting point of 208-210°C (recrystallized from methanol)
(2,6-difluorobenzyl)-5-methyl-1H-
1,2,3-triazole-4-rupoxamide was obtained.

Real IL 7-1-(2,6-difluorobenzyl)-1
2.81 g (10 mmol) of H-1,2,3-triazole-4°5-dicarboxamide, 20 mmol of acetic anhydride, and 2 drops of sulfuric acid were heated at 80° C. for 3 hours. After cooling, the mixture was stirred for 1 hour at 20 DEG -25 DEG C. with 100 DEG C. of water, and the precipitated product was filtered off with suction and washed with water. methanol 75
When recrystallized from wJ, 1-(
2,6-difluorobenzyl)-1H-1°2,3-triazole-4,5,-di(N-acetyl)carboxamide was obtained.

Practical Example 1 Once the procedure described in Example 17 was carried out, 1-(2,6-difluorobenzyl) with a melting point of 205-207°C (recrystallized from dioxane/toluene) was obtained.
1H-1,2,3-triazole-4-(N-acetyl)carboxamide was also obtained in a similar manner.

1.4 g of uniacetidine dicarboxylic acid diamide (I
2.5 mmol) in dimethyl sulfoxide Io at 60°C.
Dissolved in n/. 2.6-cyfluorobenzyl azide 1
．． 69 g (I0 mmol) were added thereto and stirred for 16 hours at 80°C. It was then diluted with 25° of water, filtered with suction, stirred with 50° of water, stirred at 50-60°C for 30 minutes, filtered again with suction, dried and recrystallized from dioxane/ethanol, with a melting point of 203-205 ℃ 1
-(2,6-difluorobenzyl)-1H-1,2,3
-triazole-4,5-dicarboxamide was obtained.

201-each 1-(o-fluorobenzyl)-1H
-1,2,3-triazole-4-carboxamide 50
Tablets containing mg were prepared as follows: Red Qi - (for I0,000 tablets) Active ingredient 500.0 g lactose
500.0g potato starch
352.0g gelatin 8.0
g Talc 60.0g Magnesium stearate 10.0g Silica (highly dispersed product)
20.0g ethanol
Sufficient amount of active ingredients including lactose and potato starch 292g
The mixture was moistened with an alcoholic solution of gelatin and granulated through a sieve.

After drying, mix the granules with remaining potato starch, talc,
Magnesium stearate and highly dispersed silica are mixed and the mixture is compressed to a weight of 14 ml each.
5.0 g to form tablets containing 50.0 mg of active ingredient. If desired, the tablets may be scored to better adjust the dosage.

Real m-each 1-(o-fluorobenzyl)-1H
-1,2,3-triazole-4-rupoxamide 10
Two compositions (for I000 tablets) of which film-coated tablets containing 0 mg can be produced as follows: Active ingredient 100.00 g lactose
100. OOg corn starch flour
70.00g talc
8.50g Calcium stearate 1.50g
Hydroxypropyl methylcellulose 2.36g Shellac 0.64g Water
Sufficient methylene
Sufficient quantities of the active ingredient, lactose and 40 g of corn starch were mixed and moistened with a paste made (on heating) of 15 g of corn starch and water and the mixture was granulated. The granulation was dried and mixed with the remaining corn starch, talc and calcium stearate.

This mixture was compressed to form tablets weighing 280 g.

The tablets were then coated with a solution of hydroxypropyl methylcellulose and shellac in methylene chloride. The final weight of the tablet was 283g.

W-Tablets and coated tablets containing the other compounds of Examples 1-19 could also be prepared as described in Examples 20 and 21.

Claims (1)

[Claims] Formula (I): ▲Mathematical formula, chemical formula, table, etc.▼(I) In the formula, Ph is fluorinated in the o-position and optionally further substituted with at least one further halogen atom. represents a phenyl residue, alk represents a lower alkylidene,
R_1 represents hydrogen, lower alkyl, or a carbamyl group unsubstituted or substituted with lower alkanoyl or lower alkyl, and R_2 represents a carbamyl group unsubstituted or substituted with lower alkanoyl or lower alkyl. Fluorinated 1-(α-phenylalkyl)-1H
-1,2,3-triazole compound. 2, Ph represents phenyl fluorinated at the o-position and optionally further substituted with up to 3 halogen atoms with an atomic number of up to 35, alk represents C_1-C_4-alkylidene, R_1 is hydrogen, C_1-C_4 - represents alkyl, carbamyl, N-C_1-C_7-alkanoylcarbamyl or N,N-di-C_1-C_4-alkylcarbamyl, R_2 is carbamyl, N-C_1-C_
7-alkanoylcarbamyl or N,N-di-C_1-
Claim 1 representing C_4-alkylcarbamyl
Compounds described in Section. 3, Ph represents phenyl fluorinated at o-position and optionally further substituted with up to 2 chlorine atoms, 1 fluorine atom and 1 chlorine atom, or up to 2 fluorine atoms, and alk is C_1-C_4-alkylidene, R_1 represents hydrogen, C_1-C_4-alkyl, carbamyl, N-C_2-C_5-alkanoylcarbamyl or N,N-di-C_1-C_4-alkylcarbamyl, R_2 represents carbamyl, A compound according to claim 1 representing N-C_2-C_5-alkanoylcarbamyl or N,N-di-C_1-C_4-alkylcarbamyl. 4, Ph represents phenyl fluorinated at the o-position and optionally further substituted with one chlorine atom, one fluorine atom and one chlorine atom, or up to two fluorine atoms,
alk represents C_1-C_4-alkylidene, R_1
represents hydrogen, C_1-C_4-alkyl or the residue R_2, R_2 is carbamyl or N,N-di-C_1-C_
A compound according to claim 1 representing 4-alkylcarbamyl. 5, Ph is o-fluorophenyl, 2,3-, 2,4-
, 2,5- or 2,6-difluorophenyl or 6
-chloro-2-fluorophenyl, alk represents methylene, R_1 represents hydrogen or carbamyl, R_
2. A compound according to claim 1, wherein 2 represents carbamyl. 6, Ph represents o-fluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl or 2-chloro-6-fluorophenyl, alk represents methylene, and R_1 and R_2 are both carbamyl A compound according to claim 1, which represents 7,1-(o-fluorobenzyl)-1H-1,2,3
-triazole-4,5-dicarboxamide. 8,1-(2,6-difluorobenzyl)-1H-1,
2,3-triazole-4,5-dicarboxamide, 1-(o-fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, 1-(2,6-difluorobenzyl)-1H-1 ,2,
3-triazole-4-carboxamide, 1-(6-chloro-2-fluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, 1-(6-chloro-2-fluorobenzyl)-1H- 1
, 2,3-triazole-4,5-dicarboxamide, 1-(2,5-difluorobenzyl)-1H-1,2,
3-triazole-4,5-dicarboxamide, 1-(2,6-difluorobenzyl)-5-methyl-1
H-1,2,3-triazole-4-carboxamide, 1-(2,6-difluorobenzyl)-1H-1,2,
3-triazole-4,5-(N,N-dimethyl)-dicarboxamide. 1-[1-(2,6-difluorophenyl)ethyl]-
1H-1,2,3-triazole-4-carboxamide, 1-{2-[2-(2,6-difluorophenyl)propyl]}-1H-1,2,3-triazole-4-carboxamide, 1 -{2-[2,6-difluorophenyl)propyl]
}-1H-1,2,3-triazole-4,5-dicarboxamide, 1-(2,6-difluorobenzyl)-1H-1,2,
3-triazole-4-(N-acetyl)carboxamide, 1-(2,6-difluorobenzyl)-1H-1,2,
3-triazole-4,5-(N-acetyl)dicarboxamide, 1-(2,3-difluorobenzyl)-1H-1,2,
3-triazole-4,5-dicarboxamide or 1-(2,4-difluorobenzyl)-1H-1,2,
The compound according to claim 1, which is a 3-triazole-4,5-dicarboxamide. 9. A pharmaceutical composition containing the compound claimed in any one of claims 1 to 8 together with conventional pharmaceutical auxiliaries and/or carriers. 10. Formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) where Ph is a phenyl residue fluorinated in the o-position and optionally further substituted with at least one further halogen atom , alk represents lower alkylidene,
Novel fluorination 1 of: R_1 represents hydrogen, lower alkyl, or a carbamyl group unsubstituted or substituted with lower alkanoyl or lower alkyl; R_2 represents a carbamyl group unsubstituted or substituted with lower alkanoyl or lower alkyl; -(α-phenylalkyl)-1H
- A method for producing a 1,2,3-triazole compound, the method comprising: a) Ph-alk-N_3(II) with the formula (III): R_1-C=C-R_2(III), where Y_1 is hydroxy; Does Y_2 represent hydrogen?
or Y_1 and Y_2 jointly represent a further bond, or a salt thereof and/or a tautomer thereof, or b) formula (IV): Ph-alk-Z(IV) In the formula, Z represents a reactive esterified hydroxyl. or c) Formula (VI): ▲Mathematical formulas, chemical formulas, tables, etc.▼(VI) In the formula, Y_4 is a residue Y_A that can be converted to carbamyl unsubstituted or substituted with lower alkyl, and Y_5 is the group R
_1 or a residue Y_B convertible to unsubstituted or lower alkyl-substituted carbamyl, or Y_4 is a group R_
2 and Y_5 represents a residue Y_B which can be converted into unsubstituted or lower alkyl-substituted carbamyl, in the compound, Y_A and/or Y_B are converted into unsubstituted or lower alkyl-substituted carbamyl,
If necessary, the isomer mixture obtained is separated into its components, the isomer of formula (I) is isolated and, if desired, the reaction product obtained by each method is converted into other isomers of formula (I). and/or dividing the enantiomer mixture or diastereomer mixture obtained by each method into each component, in particular a method of formula (VI) (wherein Y_4 is esterified carbamyl and Y_5 is hydrogen, lower alkyl or esterified carboxy) with excess ammonia or di-lower alkyl amine, and if desired, the compound obtained by each method (where R_2 and optionally R_1 are R represents unsubstituted carbamyl)
A manufacturing method characterized by converting _2 and R_1 in some cases into lower alkanoyl.